Mechanoresponsive Carbamoyloximes for the Activation of Secondary Amines in Polymers

Abstract Mechanophores are molecular moieties that are incorporated into polymers and respond to force with constitutional, configurational, or conformational bond rearrangements to enable functionality. Up to today, several chemically latent motifs have been activated by polymer mechanochemical methods, but the generation of secondary amines remains elusive. Here we report carbamoyloximes as mechanochemical protecting groups for secondary amines. We show that carbamoyloximes undergo force‐induced homolytic bond scission at the N−O oxime bond in polymers thus producing the free amine, as the reaction proceeds via the carbamoyloxyl and aminyl radicals, analogously to its photochemical counterpart. Eventually, we apply the carbamoyloxime motif in a force‐activated organocatalytic Knoevenagel reaction. We believe that this protecting strategy can be universally applied for many other secondary and primary amines in polymer materials.

S4 all the photochemical experiments where the irradiation source was indicated as "high intensity". Every experiment was performed by irradiating a capped quartz cuvette (d = 1.00 cm) located below the lamp at a distance of approximately 5 cm (at this distance, the intensity was found be in a range of 0.6-0.8 mW•cm -2 , measured with a radiometer). Every irradiation was performed at room temperature and covering the whole system with a proper box. The relative high intensity of this irradiation source is given by the total integral of the emission spectra, where its peak is at 254 nm. This setup was more appropriate when higher concentrations of the sample were required (e.g., for NMR analysis, chemical derivatization, catalytic trials).
Low intensity: the irradiation source was a LOT-ORIEL high-pressure Hg lamp (500 W). The peak of the emission spectrum at 254.65 nm was selected through a monochromator, whose outlet was connected to an optical fiber, in turn connected to a cell holder located inside a spectrometer for in-line measurements. This setup was used for every experiment where the irradiation source was indicated as "low intensity". A capped quartz cuvette (d = 1.00 cm) was placed inside the thermostat holder and irradiated at 25 °C. The relative low intensity of this irradiation source is given by the narrow integral of the filtered light through the monochromator. This setup was more appropriate when low concentrations were required (e.g., UV-vis absorption spectroscopy).
Single UV-vis absorption measurements were performed in a capped quartz cuvette (d = 1.00 cm) on a Thermo Evolution 300 spectrometer. UV-Vis absorption measurements during irradiation were performed in a capped quartz cuvette (d = 1.00 cm) on an Agilent Cary 60 spectrometer equipped with a Peltier thermostated cell holder.

Ultrasonication
Ultrasonication experiments were carried out with a Sonic VCX 500 ultrasonic processor purchased from Sonics & Materials, equipped with a 13 mm probe, at f = 20 kHz and applying a pulse of 1 s "on", 1 s "off". The amplitude was set at 30% (IP = 7.4 W•cm -2 ) or 60% (IP = 17.8 W•cm -2 ). The power intensities IP were determined by a proper calibration using an established calorimetric method. [1] Samples were injected in a 50 mL Suslick vessel (from Sonics & Materials or from Zinsser Analytic), bubbled with N2 for 10 min, sealed, and sonicated in a H2O-ice bath (2-8 °C). Prior to every subsequent experiment, every solution was filtered to remove metallic particles released by the probe. In case of sonication in THF, DMF, THF/H2O mixture, the filtration was carried out with a CHROMAFIL PTFE membrane with 0.45 µm pore size. In case of pure H2O, the filtration was carried out with a CHROMAFIL PA membrane with 0.45 µm pore size. Organic solvents were used at p.a. grade, while H2O was used at HPLC grade. Carbonyldiimidazole (CDI, 874 mg, 5.39 mmol, 1.1 equiv.) was suspended in dry THF (10 mL). 4-piperidinethanol 1 (633 mg, 4.90 mmol,1.0 equiv.) was then added to the mixture; which was stirred and refluxed for 16 h under N2 stream. Afterwards, all volatiles were removed in vacuo, the obtained oil was dissolved in CH2Cl2 (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). The aqueous phase was extracted with more CH2Cl2 (20 mL) and the organic layers were collected and dried over MgSO4. After filtration, the solvent was removed in vacuo. The final product was obtained without further purification (clear oil, 82%).

Carbamoylimidazolinium salt 3
Carbamoylimidazole 2 (669 mg, 3.00 mmol, 1 equiv.) was dissolved in dry MeCN (6 mL) in a Schlenk flask under N2 atmosphere. MeI (747 µL, 12.00 mmol, 4 equiv.) was slowly injected and the mixture was then stirred at r.t. for 24 h, observing the coloration of the solution slowly turning to light yellow. All the volatiles were removed in vacuo to yield the final product without further workup (yellow solid, quant.).

Carbamoylimidazole 11
Carbonyldiimidazole (CDI, 1.42 g, 8.80 mmol, 1.1 equiv.) was suspended in THF dry (15 mL), piperidine (790 µL, 8.00 mmol, 1 equiv.) was then added to the mixture; this latter was stirred and refluxed for 16 h under N2 stream. Afterwards, all volatiles were removed in vacuo, the obtained oil was dissolved in CH2Cl2 (30 mL) and washed with H2O (2×20 mL) and brine (20 mL). The aqueous phase was extracted with more CH2Cl2 (50 mL), the organic layers were collected and dried over MgSO4. The salt was filtered off, the solvent was removed in vacuo, and the product was obtained without further purification (clear oil, 85%

Control initiator 15
Ethylene glycol (900 µL, 16.11 mmol, 1 equiv.) and dry Et3N (4.65 mL, 32.22 mmol, 2 equiv.) were dissolved in dry THF (80 mL) in a Schlenk flask under N2 atmosphere. Subsequently, a solution of α-bromoisobutyryl bromide (3.89 mL, 32.22 mmol, 2 equiv.) in dry THF (20 mL) was added dropwise over 30 min at 0 °C. Then, the mixture was stirred at r.t. overnight. Afterwards, all the volatiles were removed in vacuo, the residue was dissolved in EtOAc (100 mL), washed with H2O (30 mL), sat. aq. NaHCO3 sol. (30 mL), and brine (30 mL). The organic layer was dried over MgSO4 and the salt was filtered off. The solvent was removed in vacuo and a further purification by column chromatography (silica, EtOAc:heptane = 1:1) afforded the final product (white ductile solid, 38%).  Afterwards, all the volatiles were removed in vacuo, the residue was dissolved in CH2Cl2 (40 mL) and washed with H2O (20 mL) and brine (20 mL). The parent aqueous layers were collected and extracted with more CH2Cl2 (30 mL). The organic layers were collected, dried over MgSO4 and the salt was filtered off. The solvent was removed in vacuo and the final product was obtained without further purification (white solid, 78%). The selected initiator was dissolved in a small amount of DMSO and different stock solutions of CuBr2 and Me6TREN in DMSO, previously prepared, were collected; in parallel, the inhibitor was removed from the monomer by means a short column of neutral Al2O3. Then, in a Schlenk tube with proper size, the initiator solution, two aliquots of respectively CuBr2 stock solution and Me6TREN stock solution, and the monomer, were mixed, eventually adding an amount of DMSO necessary to reach a total volume of this latter equal to the volume of the monomer. The mixture was degassed by three freeze-pump-thaw cycles, after which the stir bar, having the activated Cu 0 -wire (approximately 5 cm) wrapped around it, was added to the Schlenk tube and kept anchored to the glass wall through an external magnet; subsequently, three more freeze-pump-thaw cycles were performed. Then, the stir bar with the Cu 0 -wire was dropped into the degassed mixture, which was left stirring at r.t. for 6 h, observing the solution getting more viscous. Afterwards, the mixture was diluted in THF and filtered over neutral Al2O3. The solvent was removed in vacuo and the viscous residue was precipitated in cold MeOH (2×) to yield the final polymer. Eventually, the polymer was dialyzed against MeCN overnight.

Purification of hydroxyethyl acrylate
The monomer HEA was purified prior to use, to remove residues of diacrylate side product, according to literature. [2] A monomer solution was diluted in H2O (20% v/v), extracted with heptane (10×50 mL); the aqueous layer was salted with NaCl, to reach approximately 200 g•L -1 , and extracted with Et2O (4×200 mL). Afterwards, Hydroquinone (0.05 wt%) was added to the organic layer, which was dried over MgSO4 and the salt was filtered off. The solvent was removed in vacuo to yield the final pure liquid HEA, which was safely stored at 2-8 °C in the dark.

General procedure for Cu 0 -mediated CRP with hydroxyethyl acrylate (HEA)
The procedure of the CRP with HEA to synthesize polymers with high molar masses was reproduced according to the literature. [2] The selected initiator was dissolved in a small amount of DMSO and a stock solution of Me6TREN in DMSO, previously prepared, was used. The inhibitor was removed from the purified monomer by means a distillation in vacuo (max. 65 °C at 0.001-0.010 mbar). Then, in a Schlenk tube with proper size, the initiator solution, an aliquot of Me6TREN stock solution, and the monomer, were mixed, eventually adding an amount of DMSO necessary to reach a total volume of twice the volume of the monomer. The mixture was degassed by three freeze-pump-thaw cycles, after which the stir bar, having the activated Cu 0 -wire (approximately 5 cm) wrapped around it, was added to the Schlenk tube and kept anchored to the glass wall through an external magnet. Subsequently, three more freeze-pump-thaw cycles were performed. Then, the stir bar with the Cu 0 -wire was dropped into the degassed mixture, which was left stirring at r.t. for 6 h, observing the solution getting more viscous. Afterwards, the mixture was precipitated in cold Et2O, the residue was dissolved in H2O, dialyzed overnight against H2O, and freeze-dried to yield the final polymer. S11

Synthesis of PMA6107
The synthesis was performed according to the general procedure (cf. Section 2.2.2). A degassed solution containing the carbamoylaldoxime mechanophore initiator 6 (15.1 mg, 0.025 mmol, 1.00 equiv.), MA monomer (2.26 mL, 25.00 mmol, 1000 equiv.), CuBr2 (1.25 µmol, 0.05 equiv.), Me6TREN (3.75 µmol, 0.15 equiv.), and Cu 0wire, in DMSO (2.26 mL) was stirred at r.t. for 6 h. After workup, the polymer was obtained. Mn = 107.0 kDa and ĐM = 1.20 ( Figure S84). NMR spectra ( Figure S83) are reported with the zoomed aromatic region and it shows a low appearance of new aromatic peaks which are attributed to a small degree of thermal conversion to the nitrile product PMA7 caused by local high temperature in the polymerization mixture due to the intrinsic exothermicity of the reaction (cf. section 2.3 for more information). For the same reason, the GPC spectra in Figure S84 presents a small shoulder at lower molar mass, attributed to the half-length polymer chain having the nitrile functionality as end group.

Synthesis of PMA6 with different molar masses
Following the same procedure as for PMA6107, but varying the equivalents of the monomer and keeping the Schlenk flask immerged in a H2O bath to maintain thermostatic conditions, multiple polymers with different molar masses were obtained (PMA680, PMA690, PMA6145, PMA6134, PMA6116, PMA650), observing a generally lower conversion compared to PMA6107. Table S1 summarizes the results, with reference to the GPC and NMR analysis Figures of every polymer. Every NMR spectrum is reported with the zoomed aromatic region to evidence the structural integrity of the mechanophore initiator. For all the polymers prepared in thermostatic conditions, no appearance of new aromatic peaks was observed.

Chain-terminal control PMA14
The synthesis was performed according to the general procedure (cf. Section 2.2.2). A degassed solution containing the carbamoylaldoxime control initiator 14 (5.1 mg, 0.0125 mmol, 1.00 equiv.), MA monomer (1.13 mL, 12.50 mmol, 1000 equiv.), CuBr2 (0.63 µmol, 0.05 equiv.), Me6TREN (1.88 µmol, 0.15 equiv.), and Cu 0 -wire in DMSO (1.13 mL) was stirred at r.t. for 6 h. After workup, the polymer was obtained. Mn = 58.7 kDa and ĐM = 1.14 ( Figure  S98). NMR spectrum ( Figure S97) is reported with the zoomed aromatic region to show the integrity of the control initiator. A low appearance of new aromatic peaks which are attributed to a small degree of thermal conversion to the nitrile product, most likely caused by local elevated temperature in the polymerization mixture due to the intrinsic exothermicity of the reaction.

Thermal stability experiments
According to the literature, [3,4] different oxime derivatives show also a partial thermal responsiveness, whose kinetics is normally much slower than for the photochemical pathway, and very high temperature are necessary to achieve high conversions. Therefore, the thermal sensitivity at elevated temperature and stability over longterm storage was investigated for the carbamoylaldoxime motif in question.
The initiator 6, after approximately 8 months of storage at 2-8 °C, was analyzed by 1 H-NMR ( Figure S1), which does not show any conversion or degradation of the aromatic region, confirming its stability in these storage conditions over long term. Similarly, the integrity of the structure was also evaluated incorporated in the middle of linear polymer chains. Therefore, both PMA6 and PHEA6 were analyzed by 1 H-NMR spectroscopy ( Figure S2 and Figure  S3), showing that they are both stable after 4 months of storage at 2-8 °C, and also after 4 d in DMSO-d6 at r.t. exposed to visible light. In Figure S2, residues of solvents are present, DMF at δ = 7.95 ppm, and CHCl3 at δ = 8.32 ppm.
Then, the thermal responsiveness at higher temperatures was evaluated for the molecule 5. An NMR sample of this latter in DMSO-d6 was left at 70 °C for 6 h. Thereafter, the 1 H-NMR spectrum was recorded ( Figure S4) showing a low appearance of the peaks related to the nitrile 7. However, their intensity suggests that this thermal process occurs with very slow kinetics, and very high temperature are required. Furthermore, concerning the synthesis of 5 and its photochemical experiments reported in the related Section 2.4, the removal of the solvents in vacuo (THF and DMF), always done at a maximum of 50 °C for maximum 1 h, was never characterized by some conversion of the molecule to the related nitrile. Generally, complete stability was confirmed by consulting the corresponding 1 H-NMR spectra after staying in the hot H2O bath during the evaporation process. However, as already mentioned in Section 2.2, different batches of this latter were made keeping the mixture in a H2O bath to maintain thermostatic conditions to avoid possible local exothermic heating, which realistically affected the purity of the isolated PMA6107.
An extreme study of the thermal responsiveness of 5 was performed by simply submitting it to a GC-MS analysis, whose conditions of vaporization are reported to reach the temperature of approximately 250 °C. As shown in Figure S5, the final chromatogram does not show any residual 5, but only the products amine 1 and nitrile 7, demonstrating that the thermal pathway at extreme conditions affords the same products as the photochemical one.         The excitation of the oxime derivatives triggers a photoinduced homolytic scission of the oxime N-O bond, generating an iminyl radical on one side, and another radical, which depends on the compound subclass, on the other side. The iminyl radical can undergo three different pathways, depending on the structure and on the external conditions: i.
the hydrogen radical abstraction, to give the imine functional group, ii.
the cyclization through 5-exo or 6-endo, if a double bond is present in the structure, and iii.
the dissociation to give the nitrile functional group, which mostly happens when the starting oxime presents an aldehyde-like structure (aldoxime), [5] therefore reducing the lifetime of the iminyl radical, that becomes less prone to undergo cyclization or H-abstraction, which are instead more favored when the oxime presents a ketone-like structure (ketoxime).
The nature of the other radical will determine the final product on the other side, depending on the compound subclass. Among different ones accurately summarized in literature, [3] the most significant ones which have been studies are the oxime esters, oxime ethers, and oxime carbamates (or carbamoyloximes), which is the one that is subject of this work. The detailed mechanism of the photochemical decomposition of these carbamoyloximes concerns the formation of the iminyl radical and of the carbamoyloxyl radical. This latter is known to be extremely unstable and prone to undergo an immediate decarboxylation, [6] as shown, to give the aminyl radical. This, in turn, exhibits longer lifetimes, but as soon as it can abstract an hydrogen radical from its surrounding, it affords the final amine. [7]

General procedure and list of experiments
The experiments were carried out on different structures synthetized and in different conditions, moreover, different analytic techniques were used depending on the purpose of the specific photochemical experiment. Therefore, multiple entries were created, and these are summarized in Table S2. Two different light sources (cf. Section 1.1 for details) were used for different entries, depending on the concentration of the sample and on the intrinsic kinetics of the compound for the photochemical reaction. When high concentration was required and/or the kinetics were specifically slow, the high intensity UV source was used. On the other hand, the low intensity UV source was always used when the concentration was in UV-vis spectroscopy range. All experiments were performed in a Quartz cuvette. In case of the low intensity source (coupled with a spectrometer), the cuvette was kept in thermostatic conditions at 25 °C and equipped with a stir bar, so that the solution was constantly stirred during the whole photochemical experiments. In case of the high intensity source, the cuvette was placed below the beam source (at a distance of 5 cm), the system was properly isolated in the dark, and the irradiation was performed without magnetic stirring and without thermostatic conditions. To aid the reaction, the mixture in the cuvette was manually mixed at regular intervals and the temperature of the solution was measured and verified to never exceed a maximum of 31 °C after 60 min of irradiation. This temperature effect could be neglected in terms of ability to compete for the photochemical conversion of the molecule in question.

Small molecules: the iminyl pathway
The UV-vis absorption spectra of 5 were recorded during irradiation of the sample in: THF (Entry 1 of Table S2; UVvis absorption spectra in Figure S6), H2O (Entry 2 of Table S2; UV-vis absorption spectra in Figure S7), and DMF (Entry 5 of Table S2; UV-vis absorption spectra in Figure S8). During the irradiation, the general trend is in agreement with previous studied reported in the literature with similar structures. [8] Either in THF or H2O, the main peak at 262 nm is decreasing, while the shoulder on the left, at around 230 nm, is increasing in both solvents.
The shoulder at higher wavelengths (around 310 nm) is significantly increasing in H2O, while only slightly in THF. Furthermore, looking at the ratio between the main band and the shoulders, the kinetics in H2O appear to be faster than in THF, considering the starting identical conditions. To conclude, the irradiation was also performed in DMF, but since DMF also absorbs UV light at around 254 nm, no significant change of the spectra (the region of the shoulder at higher wavelengths was monitored) was observed. This may well be due to the lack of absorbed photons by the molecule in question, because of the low intensity light source, thus low density of irradiation, and low concentration of the sample.
The exact photochemical outcomes of 5 for the pathway of the iminyl radical intermediate was semi-quantitatively investigated through a detailed 1 H-NMR analysis of the aromatic region. First, the study was performed in THF and H2O, reproducing the same irradiation conditions used for the UV-vis absorption monitoring (respectively Entry 1 and Entry 2 of Table S2). In this case, for each entry three batches of samples were collected for a total of approximately 9 mL. The solvent was then removed in vacuo and the residue was dissolved in DMSO-d6 for 1 H-NMR analysis, which was ran over 128 scans given the low amount of the sample and the necessity to have an acceptable resolution for the semi-quantitative survey. The results are summarized in Figure S9. The starting molecule 5 has its set of aromatic peaks at δ = 8.59, 7.66, and 7.43 ppm (i, g, and h in Figure S9b), but after irradiation in THF we recognize only one new set of aromatic peaks at δ = 7.78 and 7.52 ppm (g' and h' in Figure  S9b), which are attributed to the nitrile compound 7. The result is very similar when the irradiation is carried out in H2O, where the nitrile 7 is the main product obtained. The only difference is that there is another set of new aromatic peaks at δ = 7.58, 7.49 and 7.28 ppm (indicated as black dots in Figure S9b), whose structural elucidation remains unknown. A possibility is that they are related to a product derived from a diradical coupling between two intermediates, for instance the aminyl and iminyl radicals, as already reported in literature for similar classes of oxime derivatives. [3,8] Concerning the intensity of the peaks, we can observe that in case of irradiation in H2O more starting molecule 5 has been converted, which is in agreement with the observation done for the UV-vis absorption results.

S20
Regarding the irradiation of 5 in DMF, no response was observed at low concentration as commented above (Entry 5 of Table S2; UV-vis absorption spectra in in Figure S8). Therefore, the photochemical activity in this solvent was tested in different conditions using a high intensity light source and increasing the concentration of the sample (Entry 6 of Table S2). After the irradiation, the sample was collected and the solvent was removed in vacuo. The residue was dissolved in CDCl3 for 1 H-NMR analysis, the results are summarized in Figure S10. The starting molecule 5 has its aromatic peaks at δ = 8.32, 7.72, and 7.42 ppm (i, g, and h in Figure S10b), but after irradiation the partial appearance of new aromatic peaks at δ = 7.64 and 7.49 ppm (g' and h' in Figure S10b) is observed, which are assigned to the nitrile 7. Residual CHCl3 is present at δ = 7.26 ppm, while residues of DMF can also be identified at δ = 8.02 ppm. To conclude, we were able to verify that, when the intensity of irradiation and the concentration of the sample are high enough to permit the molecules of 5 to absorb photons, these can undergo photochemical decomposition in DMF in the same way as they do in THF and H2O. Here, the nitrile 7 is also the only aromatic product observed.     Table S2) was collected and the solvent (THF) was removed in vacuo. The residue was re-dissolved in MeCN for the final preparation required for the MS analysis. ESI + HRMS was performed, and results are reported in Figure S11. This analysis can only be used for a qualitative and semi-quantitative evaluation of the amine formation, but no exact quantitative information can be extracted. Figure S11a shows the spectrum of only 1 as control, while Figure S11b shows the spectrum of pristine 5. Figure S11c is the spectrum of the irradiated sample, where we can clearly see a significant increasing of the peak at m/z = 130.12, which is attributed to the MH + of the compound 1. The intensity of the latter, after irradiation, is approximately 6 times lower than the peak of the reference (considering the same initial concentration in mg•mL -1 ). However, the information is only semi-quantitative. Moreover, it must be taken into account that the photochemical conversion is only partial, besides that the starting equal concentration in mg•mL -1 means that the final molarity of the amine is lower, due to the lower molar mass.

1 H-NMR after derivatization with cyclic carbonate 16
This approach was chosen given the difficult interpretation of direct 1 H-and 15 N-NMR of the produced amine in low concentrations. The 1 H-NMR result of a first test reaction carried out directly in CDCl3 (0.5 mL), between piperidine (1 mM) and the carbonate 16 (10 mM), is reported in Figure S12. The NMR spectra clearly show the diagnostic upfield shift: before the addition of the piperidine, the merged peaks of the four protons of 16 are only present at δ = 7.30-7.20 ppm. After the addition of the amine, the pattern of the final adduct piperdine-16 can be clearly recognized at δ = 7.09, 7.02, and 6.91 ppm (o, o', o'', and o''' in Figure S12b). The spectra also present side peaks attributed to degradation products of 16 deriving from hydrolysis/oxidation processes (black dots in Figure  S12b). Therefore, it must be considered that this molecule 16 requires storage at -20 °C and under dry and inert atmosphere. Its high reactivity is reflected in high tendency to hydrolyze to the corresponding catechol, which is then prone to oxidize/polymerize in presence of oxygen and at higher temperatures, giving rise to a mixture of broad aromatic signals. These can be already partially observed in the spectra in Figure S12b.
The chemical derivatization with 16 was then applied to the irradiated 5 in THF (Entry 4 of Table S2). In this case, the solvent was first removed in vacuo, the residue was re-dissolved in a freshly prepared solution of 16 in excess (3 mg) in CDCl3 (0.6 mL). This was directly submitted to 1 H-NMR analysis, the results are shown in Figure S13. A control solution, prepared from pristine 5 (3 mg) and 16 (3 mg) in CDCl3 (0.5 mL), was also submitted to 1 H-NMR analysis. Observing the comparison of the NMR spectra ( Figure S13b) it can be seen that before irradiation the only peaks present are related to 16 in the range δ = 7.30-7.20 ppm and to 5 at δ = 7.70 and 7.42 ppm (g and h in Figure S13b). After irradiation, the peaks of nitrile 7 at δ = 7.63 and 7.49 ppm (g' and h' in Figure S13b Table S2), the carbonate 16 (4 mg) was added. Then, the solvent was removed in vacuo, the final residue was re-dissolved in CDCl3 (0.5 mL), and submitted to 1 H-NMR analysis. Again, a control solution of 14 (3 mg) and 16 (4 mg) was prepared in DMF, the solvent was removed in vacuo, the residue redissolved in CDCl3, and submitted to 1 H-NMR analysis. The results are shown in Figure S14. The NMR spectra in Figure S14b present a significant decrease of the peak of 16 in the range of δ = 7.20-7.30 ppm, while peaks deriving from its thermal decomposition during the solvent evaporation emerge (black dots in Figure S14b). Before irradiation, only the starting aromatic peaks of 14 are visible at δ = 7.72 and 7.42 (g and h in Figure S14b). However, after irradiation a partial appearance of the aromatic peaks of the nitrile 9 at δ = 7.66 and 7.50 (g' and h' in Figure  S14b

Linear polymers
Analogously to small molecule 5, the photochemical activity of PMA6 and PHEA6 was verified by UV-vis absorption spectroscopy over the course of irradiation with light in both THF and H2O ( Figure S15 and Figure S16).
After confirming the photochemical activity, the pathway of the iminyl radical intermediate was studied by a detailed 1 H-NMR analysis of the aromatic outcomes for the irradiated polymers PMA6 and PHEA6 (applying 128 scans for a good resolution of the low intensity peaks of the initiator). The experiments were conducted again in the three solvents THF, DMF, and H2O. We focus here on the experiments performed in THF (Entry 8 of Table S2). Therefore, three irradiated batches of 3 mL each were collected together, the solvent was removed in vacuo, the residue was dissolved in DMSO-d6, and the sample was submitted to 1 H-NMR analysis. As shown in Figure S17, the irradiation of PMA6 in THF also yields PMA7 as sole product. Exactly the same procedure was repeated for the irradiated PHEA6 in H2O (Entry 11 of Table S2) and is discussed in the manuscript. The irradiation of PMA6 in DMF (Entry 10 of Table S2) was performed with a high intensity light source. After the irradiation, the DMF was removed S29 in vacuo, the residue was dissolved in DMSO-d6, and the sample was submitted to 1 H-NMR analysis, as discussed in the manuscript.  Table S2) at different irradiation times.  Table S2).

Ultrasonication experiments 2.5.1. General procedure and list of experiments
The investigation of the mechanochemical scission process was conducted by a series of ultrasonication experiments under varying conditions (Table S3). A specific set of sonication parameters and experimental steps was maintained fixed for the entries 1-14: f = of 20 kHz, amplitude of 30%, and pulse sequence 1 s "on" and 1 s "off", while the volume of the sonicated solution was always 10 mL. For entry 15, which represents an important control experiment, the conditions of sonication were kept similar to the ones used for the sonication of polymer PMA6 in question, subsequently used for the catalysis trials (see experiments in Table S6, in section 2.8.1). These conditions were the following: pulse sequence was kept at 1 s "on" and 1 s "off", amplitude was increased to 60%, and volume was increased to 30 mL.   Table S3 that were sonicated in THF, DMF, or THF/H2O mixtures were filtered through a PTFE membrane filter after sonication to remove metallic residues from the sonicator probe. Afterwards, a small volume (to reach 5 mg of polymer) was collected for GPC analysis. Therefore, the solvent was removed in vacuo, the final residue was re-dissolved in THF (for GPC, 1 mL), and submitted to the analysis. The rest of the sample, containing most of the polymer, was dialyzed against MeCN. From the final solution, the solvent was removed in vacuo and the residue was re-dissolved in DMSO-d6 for 1 H-NMR analysis with 128 scans for the visualization of the initiator in the aromatic region.
For the samples sonicated in pure H2O (Entry 10 and 12 of Table S3), the final solution after sonication was filtered through a PA membrane filter. A small volume (to reach 5 mg) was collected for GPC analysis, the solvent was removed by freeze-drying, the final residue was re-dissolved in DMF (for GPC, 1 mL), and submitted to the analysis.

S32
The rest of the sample, containing most of the polymer, was dialyzed against H2O. From the final solution, the solvent was removed by freeze-drying and the final residue was re-dissolved in DMSO-d6 for 1 H-NMR analysis, again applying 128 scans. For the UV-vis absorption analysis, a second batch of the samples was sonicated. Again, the solution was then filtered and dialyzed as described above. Afterwards, the final solution was adjusted to the initial volume (10 mL) to maintain the initial concentration. Then volume fraction of this solution was used for the optical analysis in comparison with the pristine, non-sonicated polymer.

Mechanochemical activity
1 H-NMR and GPC samples were prepared according to the general procedure. The evidence of the mechanochemical activity of the mechanophores PMA6 and PHEA6 was shown by NMR and GPC, discussed in the main manuscript. Concerning the sonication of PHEA6 in H2O (Entry 10 of Table S3), the additional UV-vis absorption spectra are depicted in Figure S18. In this case, GPC was not the ideal method because any reference polymer sonicated in H2O would show a lot of unselective cleavage due to the high tensile force applied to the chains. Therefore, it would be difficult to extract information concerning the possible cleavage of the mechanophore. Hence, UV-vis absorption spectra were recorded before and after sonication, from which a decrease of the peak at 262 nm can be discerned. In contrast, the sonication of the chain-terminal control PHEA14 does not give any significant change in the UV-vis absorption spectrum ( Figure S34).  Table S3).

Influence of ultrasonication parameters
The mechanochemical scission kinetics of the carbamoylaldoxime mechanophore were investigated by sonicating PMA6 in different conditions. 1 H-NMR samples were prepared according to the general procedures (cf. Section 2.5.1). Comparison of the spectra for different entries are reported. Figure S19 (comparison between Entry 3, 4, and 5 of Table S3) concerns the sonication in THF for different durations and with different Mn of the polymer chain. Both Figure S20 (comparison between Entry 6 and Entry 7 of Table S3) and Figure S21 concern the sonication with different solvents THF/H2O at different ratios and DMF.
Even though the sonication performed in THF gives lower kinetics than DMF, the nitrile PMA7 is the aromatic product in both solvents. The mechanochemistry of PMA6 was additionally studied in the mixture THF/ H2O; the S33 addition of H2O was reflected by additional peaks emerging at δ = 7.93 and 7.59 ppm (a'' and b'' in Figure S21b), which are assigned to aldehyde PMA8 (see Figure S21a).  (Entry 14 of  Table S3, and Figure S35). From top to bottom: pristine PMA680, PMA680 sonicated in THF for 2 h (Entry 3 of

Mechanochemical selectivity
The summary of the calculated data concerning the selectivity study is reported in Table S4. 1 H-NMR and GPC samples were prepared and analyzed according to the general procedure (cf. Section 2.5.1). The peak integrals of the aromatic products in the 1 H-NMR spectra were used to determine the fraction of cleaved mechanophore (PMA6 or PHEA6), further divided in the fraction of the nitrile (PMA7 and PHEA7) and fraction of the aldehyde (PMA8 and PHEA8). The fraction of total scission was calculated from GPC by the starting Mn (Mn,start) and the Mn after sonication (Mn,end) of the polymer according to the following equation: [9] fraction of total scission = ,end −1 H-NMR integrals and GPC elugrams of Entry 2, 5, 7, and 10 of Table S3 and Table S4 are depicted from Figure S22 to Figure S29. From these data, the final selective scission represents the percentage of the selectively cleaved mechanophore in a sample of n polymer chains at the desired bond (oxime bond) out of the total number of scission events along the polymer chain in the same sample of n polymers. This scission selectivity (in %) was calculated as follows: selective scission = fraction of cleaved mechanophore fraction of total scission ⋅ 100  Figure S22. 1 Table S3 and   Table S3 and Table S4, dashed line).

H-NMR spectrum in DMSO-d6 with integral analysis of Entry 2 in
S38 Figure S24. 1 Table S3 and   Table S3 and Table S4, dashed line).

H-NMR spectrum in DMSO-d6 with integral analysis of Entry 5 in
S39 Figure S26. 1 Table S3 and   Table S3 and Table S4, dashed line).

H-NMR spectrum in DMSO-d6 with integral analysis of Entry 7 in
S40 Figure S28. 1 H-NMR spectrum in DMSO-d6 with integral analysis of Entry 10 in Table S3 and   Table S3 and Table S4, dashed line).

Complete NMR analysis after irradiation and sonication (Figure 1c,d)
Here ( Figure S30 and Figure S31) is reported a more complete NMR analysis of the Figure 1c and 1d (main manuscript), by stacking and comparing the synthetized reference compound PMA7, PMA8, PHEA7, PHEA8.  Table S3 and Figure S35). From top to bottom: pristine PMA6145, PMA6145 sonicated in DMF for 5 h (Entry 2 of Table S3), PMA6145 irradiated in DMF for 1 h (Entry 10 of Table S2), pristine PMA7, pristine PMA8. Figure S31.  H-NMR and UV-vis samples were prepared and analyzed according to the general procedure (cf. Section 2.5.1). Control experiments are required to prove that the scission of the mechanophore by sonication is a mechanochemical process caused by the tensile force applied to the polymer chains. Therefore, polymers bearing the mechanophore as end group in a chain-terminal position were synthesized (PMA14 and PHEA14, cf. Section 2.2). 1 H-NMR measurements over the course of the sonication of these control polymers (Entry 11 and 12  of Table S3) are reported in Figure S32 and Figure S33. The final spectra after sonication resemble those before sonication strongly suggesting that the mechanophore was not activated. Furthermore, for the sonicated PHEA14 the UV-vis absorption analysis was also performed ( Figure S34), from which we can deduce that there is no significant variation. Additionally, as further control experiment, compound 5 was sonicated under the same conditions used in Table S6, where the polymers were subsequently used for the organocatalysis experiments. These conditions are the strongest used in this work, mostly due to the high amplitude (60%), hence, an inactivity of 5 under these conditions would unequivocally reflect the mechanochemical nature of the process related to the oxime bond cleavage. As result (Figure S33d), the 1 H-NMR spectra clearly show no significant cleavage of the oxime bond, but only a neglectable presence at very low intensity of probable peaks associated with the nitrile 7, that is formed probably in very low amount during some residual thermal processes in the proximity of the cavitation bubbles, given the higher diffusion ability of the small molecule 5 compared to the mechanophore incorporated in the middle of the polymer chain.

S42
Further proof that the cleavage of the mechanophore by sonication is a mechanochemical process is provided by the result of sonicated PMA680 versus PMA6145 in THF (Entry 3 and Entry 4 of Table S3). The 1 H-NMR analysis of these two latter experiments were reported in Figure S20, where it is visible that a small amount of nitrile PMA7 has only been produced by sonicating PMA6145 while no new aromatic peaks appeared for the sonicated PMA680.
The fact that the partial cleavage of the mechanophore is only observed for the polymer with higher starting Mn represents a clear proof that the cleavage is caused by the tensile forces applied to the polymer.
An additional control experiment was performed by sonicating the polymer PMA139 (Entry 14 of Table S3) for which a detailed 1 H-NMR analysis of the aromatic region was carried out with the purpose of elucidating eventual presence of side peaks that are unrelated to the mechanophore but are present in the NMR spectra of other sonicated samples of PMA6. It was clarified that residual peaks observed in the 1 H-NMR of Entry 2, 4, and 5 of Table S3 at δ = 7.71 and 7.50 ppm (black dots in Figure 2b and Figure S19) are also present in the 1 H-NMR spectrum of sonicated PMA139 (black dots in Figure S35). This suggests that these peaks stem from impurities from the immersion probe, but are not related to the mechanophore structure and mechanochemical products.  Table S3).

Computational experiments
The qualitative simulation was carried out by CoGEF method, applied according to literature. [10] Gaussian 09 software package with GaussView implementation were used to perform the study. DFT (density functional theory) was the quantum mechanical modelling method selected, and it was used at the B3LYP/6-31G* level of theory ( Figure S36a). First, the drawn model was geometrically optimized without any constraints, obtaining the most stable local conformer. Afterwards, as starting step of the CoGEF procedure, two anchor atoms were selected, in this case the sp 3 carbon atoms of the methyl ester functional groups (blue atoms in Figure S36a). The distance between these two atoms was increased by a certain Δd, then frozen, and the geometry was optimized again, obtaining a structure slightly more constrained and with higher energy. Therefore, the distance increasefreeze-optimization cycle was repeated multiple times, varying the Δd from a maximum of 1 Å in the flat region of the energetic profile ( Figure S36b) to a minimum of 0.1 Å in the most steep region. This iteration was repeated until the breakage of the oxime bond was observed (model image in Figure S36b, O in red and N in blue), that also corresponded to a sudden drop of the energy value. Small energy drops along the energy profile were attributed to conformational variations.

Derivatization with RhBITC
The labelling reaction between the allegedly formed amine PMA1 after irradiation and/or sonication of PMA6 and Rhodamine B isothiocyanate (RhBITC) was first optimized with small molecules using piperidine (Scheme S1). Scheme S1. RhBITC forms a stable thiourea RhBpip with piperidine.
Piperidine (0.58 µL, 5.87 µmol, 1 equiv.), RhBITC (3.16 mg, 1 equiv.), and Et3N (0.82 µL, 1 equiv.) were dissolved in dry DMF (5 mL). The mixture was stirred at r.t. for 5 h, then all the volatiles were removed in vacuo, and the final residue was re-dissolved in MeCN (1 mL). To directly evaluate the formation of RhBpip, samples were withdrawn and subjected to RP-UPLC ( Figure S37), ESI + MS ( Figure S38), and UV-vis absorption spectroscopy ( Figure S39). All analyses were performed in comparison with RhBITC. The results prove the successful formation of the product, verifying the reaction conditions. Notably, when the isothiocyanate group has reacted with the amine to form the thiourea, a significant decrease of the molar absorptivity at 558 nm can be observed.
Hereafter, these conditions were applied for labeling PMA1 after irradiation and sonication of PMA6. For the former, irradiation in THF was performed (Entry 9 of Table S2), the solvent removed in vacuo, and the final polymer residue (5 mg) re-dissolved in dry DMF (1 mL). In the latter case, 2 mL were taken from the sonicated sample in THF/H2O 7:3 (v/v) (Entry 7 of Table S3), the solvent removed in vacuo, and the polymer (5 mg) re-dissolved in dry DMF (1 mL). Afterwards, RhBITC (0.34 mg, 0.62 µmol, 10 equiv. per end group) and Et3N (0.087 µL, 10 equiv. per end group) were added and left stirring overnight at r.t. Then, the solvents were removed in vacuo, the residues re-dissolved in THF (for GPC, 1 mL), and submitted to GPC analysis monitoring the UV absorption channel at 351 nm. The results are discussed in the main manuscript (cf. Figure 2). The high noise of the UV-vis signals reflect the intrinsic low sensitivity of the UV-vis detector of the GPC and the likely low yield of the labeling reaction due to the poor end group reactivity. Therefore, the detection of the amine PMA1 could only be verified qualitatively.  Table S5. Every sample was dissolved in THF and after the irradiation period an aliquot was taken and the solvent was removed in vacuo. The residue was stored and used for the subsequent catalytic experiments.
The sonication experiments were also performed similarly to the previous mechanochemical experiments (cf. Section 2.5.1), but with some important variations. The trials are summarized in Table S6. Every sample was dissolved in approximately 40 mL THF and the sonication was run for 3 h ("on" time) at 60% amplitude to significantly increase the kinetics of the scission and therefore activating larger amounts of polymer. For some trials, additional 200 µL of n-butylamine were added to the solution prior sonication. The motivations behind this experimental setup are discussed in detail in the Section 2.8.3. After the sonication, every sample was filtered through a PTFE membrane (0.45 µm) and the solution was dialyzed with an RC (regenerated cellulose) membrane (1 kDa) overnight against ca. 0.5 L MeCN to remove most of the n-butylamine excess. In the end, the solvent and most of the leftover n-butylamine were removed in vacuo and the residue was stored and used for the subsequent catalytic experiment. For the calculation of the sonicated sample concentration in the catalytic mixture, it was assumed the all polymer was retained inside the membrane. Therefore, the possible amount of polymer that leaked out of the membrane was neglected. Regarding the subsequent Knoevenagel reaction, the reaction conditions and experiment setup were reproduced similarly to a reported study. [11] CDCl3 was selected to monitor the catalytic conversion directly by submitting the reaction mixture to NMR analysis without any additional purification steps. Every experiment was carried out with the same procedure: the stored irradiated or sonicated isolated sample was dissolved in 0.6 mL of CDCl3 and the solution was then mixed with 3 mg of 4-nitrobenzaldehyde 18 giving a final concentration of 33 mM. Then, 50 equiv. of diethyl malonate 19 were added (152 µL) to obtain pseudo first-order kinetics. The mixture was stirred at room temperature and after 2 h (and 4h) and aliquot of 200 µL was removed, diluted with 0.4 mL of CDCl3, and submitted to NMR analysis with 128 scans when a more zoomed view of the cleaved mechanophore was required. A summary of the photochemically and mechanochemically triggered catalytic experiments is shown in Table S7 and Table S8. The entry numbers of the catalysis samples are the same as the related treated sample in Table S5 and Table S6. Additionally, Table S9 reports important catalytic control experiments performed. In this case, the 4-nitrobenzaldehyde 18 was first dissolved in CDCl3 and then the respective compound was added. 1 H-NMR spectroscopy was used to calculate conversions after light irradiation and ultrasonication to the active species and also to calculate catalytic conversion of the Knoevenagel reaction (Table S7 and Table S8, Figure S40 to Figure S45). A full exemplary spectrum of the Knoevenagel reaction is shown in Figure S40 (Entry 1 of Table S9) where the conversion can be calculated by comparing the integrals of the aromatic peaks of 4-nitrobenzaldehyde 18 and the coupling product 20 (signals c-b vs h-g in Figure S40). Therefore, all other spectra are zoomed in the diagnostic aromatic region. The calculation of mechanophore conversion in in Table S7 and Table S8 was carried out by comparing the integrals of the visible diagnostic aromatic signals of 5 (δ = 7.63 ppm) with the produced nitrile 7 (δ = 7.43 ppm) visible in the zoomed in spots in Figure S41c-f. In case of irradiation or sonication of PMA6, the signals taken into account were for PMA6 at δ = 7.67 ppm while for the produced end group nitrile PMA7 at δ = 7.63 ppm.
S53 Table S7. List of the catalytic experiments after irradiation with light. The concentration c1 refers to the total concentration of the mechanophore (and initiator) considering the non-cleaved and the cleaved residue. The concentration c2 refers to the concentration of the cleaved mechanophore calculated through the irradiation conversion. Table S5 compound no.   Figure S43a) -     Table S9. Exemplary analysis showing the complete assignments of the mixture containing a partial conversion of the 4-nitrobenzaldehyde 18 to the coupling product 20 with excess of the diethyl malonate 19.

Photochemically induced organocatalysis
The 1 H-NMR spectra of the catalytic experiments involving the photochemical activation of 5, in comparison to negative controls, were recorded according to the general procedure (cf. Section 2.8.1) and are shown in Figure  S41. By comparing the results in different conditions, it was observed that the high intensity light source could trigger more light-induced side reactions which reduce it final amine yield. This could be partially avoided either by increasing the irradiation concentration or by using the low intensity light source. Similar experiments were then carried out with the mechanophore-centered PMA6. The related NMR spectra, against negative controls, were recorded according to the general procedure (cf. Section 2.8.1) and are summarized in Figure S42.  Table S7). (b) Negative control pristine 5 not irradiated (Entry 3 of Table S9). (c-d) Entry 2 and 5 of Table  S7. Cleaved mechanophore 5 at different irradiation and catalytic concentrations and with different light sources.

Mechanochemically induced organocatalysis
A small amount of n-butylamine was used as scavenger of acids/electrophiles residues produced during sonication. Figure S43 reports the 1 H-NMR spectra of some key control experiments recorded according to the general procedure (cf. Section 2.8.1). The catalytic experiment carried out with the sonicated pristine 4piperidinethanol 1 in pure THF (Entry 2 of Table S6 and Table S8) shows low conversion (16%) suggesting that some residues of acids or electrophiles have been produced during the sonication and partially quenched the amine reducing its final catalytic concentration. One possible theory is that the sonication causes a very small decomposition of the glass surface resulting in the dissolution of some silica particles bearing slightly acidic silanol groups. To investigate more, solvent was removed from a pure THF sonicated solution and the residue was redissolved in water for pH measurements, as comparison, a similar water sample was prepared with a nonsonicated THF solution. However, given a non-excellent sensitivity of the instrument, no significant difference in the average pH values was obtained. Assuming that the issue is related to acidic impurities rather than electrophiles, we believe that amount of these impurities would be enough to affect the activity of very lowly concentrated amines, but without manifesting a significant pH changes when these impurities are in aqueous environment. In the future, more precise measures could be done, for instance using spectroscopic analysis of very sensitive pH indicators.
In fact, the catalytic experiments performed with sonicated PMA6 in pure THF (Entry 1 of Table S8) also showed a low conversion (11%). Therefore, the solution that was found was to use n-butylamine to maintain slightly basic conditions preventing the possible quenching of the secondary amine produced during the cleavage of the S57 sonication. As primary amine, n-butylamine cannot catalyze the Knoevenagel reaction thus not affecting the reliability of the eventual results. Even in very high concentrations, its presence in the mixture containing the Knoevenagel reagents (Entry 2 of Table S9) yields the related imine upon reaction with 4-nitrobenzaldehyde 18, while the presence of the coupling product 20 is only observed in low amount (15% conversion).
The subsequent 1 H-NMR spectra of the catalytic experiments performed with sonicated PMA6116 and PMA42 in THF containing n-butylamine were recorded according to the general procedure (cf. Section 2.8.1) and are reported in Figure S44 and Figure S45.  Table S8). (b) Sonicated pristine 4-piperidinethanol 1 in pure THF (Entry 2 of Table S8). (c) Pristine n-butylamine (Entry 2 of Table S9).